Atopic Dermatitis Epidemiology and Pathogenesis Update

特应性皮炎的流行病学和发病机理

AtopicDermatitis:

EpidemiologyandPathogenesisUpdate

LawrenceF.Eichen eld,MD,*CharlesN.Ellis,MD,

AnthonyJ.Mancini,MD, AmyS.Paller,MD,§andEricL.Simpson,MD,MCR

Theprevalenceofatopicdermatitis(AD)hasincreasedmarkedlyintheUnitedStatesoverthepast5decades,withcurrentreportsvaryingfrom10%to20%prevalenceinUSchildren,andnewdiagnosesareestimatedatalmost11%peryear.RecentresearchinADpathophysiologyandpathogenesishasdemonstratedthatADisassociatedwithepidermalbarrierdysfunctionandthatmutationsinthe laggringeneareimplicatedinbarrierdefects.ThesediscoveriesholdpromiseforfuturebreakthroughsinthediagnosisandmanagementofAD.

SeminCutanMedSurg31(suppl3):S3-S5©2012PublishedbyElsevierInc.

KEYWORDSatopicdermatitispathogenesis,barrierdefects,epidermalskinbarrier, laggringene

orldwide,theprevalenceofatopicdermatitis(AD)hasincreasedapproximatelythreefoldsincethe1960s.IntheUnitedStates,thereportedprevalenceofADcurrentlyrangesfrom10%to20%ofchildren.InarecentstudyofUSchildren17yearsofageoryoungerderivedfromNationalSurgeryofChildren’sHealthdatafrom2003,Shawandcol-leagues1reporteda10.7%prevalenceofnewdiagnosesofAD

*ProfessorofClinicalPediatricsandMedicine(Dermatology),Chief,Pedi-atricandAdolescentDermatology,UniversityofCalifornia,SanDiegoSchoolofMedicine,RadyChildren’sHospital,SanDiego,CA.

ProfessorofClinicalDermatology,AssociateChair,DepartmentofDerma-tology,UniversityofMichiganMedicalCenter,AnnArbor,MI.

ProfessorofPediatricsandDermatology,NorthwesternUniversityFein-bergSchoolofMedicine,andHead,DivisionofPediatricDermatology,Ann&RobertH.LurieChildren’sHospital,Chicago,IL.

§WalterJ.Hamlin,ProfessorandChair,DepartmentofDermatology,Pro-fessorofPediatrics,NorthwesternUniversityFeinbergSchoolofMedi-cine,AttendingPhysician,Ann&RobertLurieChildren’sHospitalofChicago,Chicago,IL.

AssociateProfessorofDermatologyandDirectorofClinicalStudies,OregonHealthandScienceUniversity,Portland,OR.

PublicationofthisCMEarticlewasjointlysponsoredbytheUniversityofLouisvilleContinuingHealthSciencesEducationandGlobalAcademyforMedicalEducationLLCinaf liationwithSkinDiseaseEducationFoundationandissupportedbyaneducationalgrantfromValeantPharmaceuticalsNorthAmericaInc.

ThefacultyhavereceivedanhonorariumfromGlobalAcademyforMedicalEducationfortheirparticipationinthisactivity.TheyacknowledgetheeditorialassistanceofJoanneStill,medicalwriter,andGlobalAcademyforMedicalEducationinthedevelopmentofthiscontinuingmedicaleducationjournalarticle.JoanneStillhasnorelevant nancialrelation-shipswithanycommercialinterests.

W

oreczemawithinthepreviousyear.(TheseprevalencedatafromthestudybyShawetalaresimilartothosereportedinpreviousstudiesinvolvingsmallerUSpopulations.2-4)

OfadditionalinterestaretwoobservationsfromthestudybyShawetal.1Oneisthattheprevalenceratesrangedfrom8.7%to18.1%fromstatetostate,withahigherprevalencealongtheEastcoaststatesandinNevada,Utah,andIdaho.Theotherobservationisthatsigni cantlyhigherdiseaseprevalencewasassociatedwithmetropolitanliving(P 0.008),blackrace(P 0.005),andeducationlevelsinthehouseholdgreaterthanhighschool(P 0.004).Thesedataclearlysuggestthatsocialorenvironmentalfactorscanaffect

LawrenceF.Eichen eld,MD,hasservedasaconsultantforAnacor,Bayer,andOnsetTherapeuticsandasaspeakerandconsultantforValeant.HehasalsobeenaninvestigatorandconsultantforGaldermaandLeoPharmaaswellasaninvestigatorforAmgen,AstellasPharmaUS,andStiefel,AGSKCompany.

CharlesN.Ellis,MD,hasservedasaconsultantforGaldermaFerndaleLaboratories,Medicis,andNovartis.

AnthonyJ.Mancini,MD,hasservedasaconsultantforQuinnovaandValeantaswellasaspeakerandconsultantforGalderma.

AmyS.Paller,MD,hasreceivedgrantresearchsupportfromAstellas.

EricL.Simpson,MD,MCR,hasservedasaconsultant,investigator,andspeakerforGalderma.

Addressreprintrequeststo:LawrenceF.Eichen eld,MD,ProfessorofClin-icalPediatricsandMedicine(Dermatology),Chief,PediatricandAdo-lescentDermatology,UniversityofCalifornia,SanDiegoSchoolofMed-icine,RadyChildren’sHospital,8010FrostStreet,Suite602,SanDiego,CA92123,Telephone:858-966-6795,x4825,Fax:858-966-4040,E-mail:

leichen eld@

1085-5629/12/$-seefrontmatter©2012PublishedbyElsevierInc./10.1016/j.sder.2012.07.002

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特应性皮炎的流行病学和发病机理

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theexpressionofAD,althoughthespeci cfactorshavenotbeenidenti ed.

ImmunologicandIn ammatoryPathways:NewerConcepts,EmergingEvidence

ADwasoncethoughttoberelatedtokeratinocytedysfunc-tion,butoverthepast2decades,theunderstandingofADpathogenesisfocusedonADasadiseaseofimmunologicdysregulation.ImmunologicstudieshavedemonstratedthatevenclinicallyunaffectedskininpatientswithADcanshowmildepidermalhyperplasiaandsparseperivascularT-cellin ltrates.Acutelyeczematousskinisassociatedwithspon-giosis,whichisamanifestationofintercellularedema.Inaddition,androgen-presentingdendriticcellsarethoughttobeofpotentialimportanceinimmunologicresponsesthatmanifestinatopicskin.However,themostrecentevolutioninunderstandingADconcernsgeneticmutationsthatcausebarrierdysfunctioninAD.ThesedevelopmentshavecalledtoquestionthecontributorstoADpathogenesis.

TheseadvancesinunderstandingADpathogenesisoc-curredfollowingtheidenti cationofasetofmutationsintheskinthatareassociatedwithbarrierdefects,speci cally,mu-tationsinthe laggringene(FLG).Interestingly,asearlyas1985,Sybertandcolleagues5hadproposedthat laggrinab-normalitieswerethecauseofichthyosisvulgaris,whichisaconditionthatwasknowntobepresentinasubsetofpatientswithAD.However,thesigni canceofthisworkwasnotappreciateduntiltherevolutioningeneticsoccurredwithinthepastdecade,withthemappingofthehumangenomeandtheidenti cationoftheFLG.WhentheworkofSybert’sgroupandotherswasrevisited,6,7itbecameclearthatFLGmutationswere,infact,thecauseofichthyosisvulgaris.(Foracomprehensivecommentaryonthisbreakthrough,Segre’sarticle,“Epidermaldifferentiationcomplexyieldsasecret:Mutationsinthecorni cationprotein laggrinunderlieich-thyosisvulgaris,”isrecommended.8)

Toreviewbrie y,thestratumcorneumlayer,alsoreferredtoastheepidermalskinbarrier,hasseveralmajorfunctions,includingthepreventionofinvasionofthebodybyenviron-mentalpathogensandthecontrolofwaterlossacrosstheepidermis(ie,transepidermalwaterloss[TEWL]).Thestra-tumcorneumconsistsofbetween10and30layers(depend-ingonanatomicsite)ofkeratinocytesthathavedifferentiatedtobecomeanucleatedcorneocytes;inthesecells,theplasmamembraneisreplacedbyalayeroflargeproteinmolecules—thecorni edenvelope.Filaggrin,anessentialstructuralpro-teininthecorni edenvelope,isexpressed rstaspro lag-grin,whichplaysanimportantrolein“packing”thekeratinocytesintothestratumcorneum.

Inadditiontoitscontributiontocreatingamortarlike,impermeablestructure, laggrinisalsobrokendown,throughproteolysis,intohumectants—hygroscopicaminoacidsreferredtoasnaturalmoisturizingfactor.Filaggrinde- ciencycanadverselyaffectthesefunctions,impairingstra-tumcorneumadhesion,enhancingTEWL,andcausingdys-

L.F.Eichen eldetal

regulationoftheskinpHresultinginincreasedskinpermeability.9

Loss-of-functionmutationsintheFLGarequitecommon:10%ofindividualsofEuropeanancestrycarrysuchmuta-tions,whichareassociatedwithareductionofabout50%in laggrinproteinproduction.7Clinically,loss-of-functionmutationshavebeenassociatedwiththedevelopmentofAD.7,10Inaddition,patientswhohaveADandtheFLGmu-tationalsohaveagreatertendencythandothosewithoutthemutationtohavemoresevereorpersistentAD,11anin-creasedriskforacquiringherpesvirusinfection(eczemaher-peticum),12andanincreasedriskforearlysensitizationandmultipleallergies(includingpeanutallergy)andasthma.10,13

Itisnowrecognizedthatavarietyofcytokinesmaymedi-atein ammationinatopicskin.AcuteADmaybeassociatedwithT-helpertype2(TH2)cytokines,includinginterleukin(IL)-4andIL-13,whichin uenceimmunoglobulinEsynthe-sisandadhesionmoleculeexpression.Inaddition,IL-31hasbeenidenti edasauniqueTH2cytokinethatisassociatedwiththedevelopmentofdermatitisandpruritusinexperi-mentalanimals.

Further,recentstudieshavedemonstratedthatthymicstromallymphopoietin(TSLP)maybeexpressedinkeratin-ocytes,affectedbyskinbarrierdefects.TSLPmaymediatein ammationoftheskinandotherorgans,includingthebronchialtree.14

MicrobesinAD:RecentFindings

ColonizationwithStaphylococcusaureusisverycommoninAD,andpatientswithADareatincreasedriskforimpetig-inizedlesions,pustules,and,occasionally,moresigni cantskinorsystemicinfections.

Withtheemergenceofcommunityepidemicsofmethicil-lin-resistantS.aureus(MRSA),concernwasraisedthatpa-tientswithADmightbeparticularlysusceptibletosuchin-fections.However,severalstudieshavefoundthattheactualratesofMRSAinfectionsinpatientswithADarenotespe-ciallyhigh;infact,comparedtoclinicalinfectionsseeninnonatopiccommunitymembers,patientswithADmorecommonlyhavemethicillin-sensitivestaphylococcalinfec-tionsthanMRSA.15,16

Ithasalsobeenshownthatthecutaneousimmunedefenseisin uencedbyinnatedefenseproteinsintheskinandthatarelativede ciencyofantimicrobialpeptidescanbeseenintheskinofpatientswithADcomparedtopatientswithotherin ammatoryskindiseases.Thisde ciencymaybeassoci-atedwithstaphylococcalcolonization.17

Interestingly,recentstudieshaveshownthatthereisaninteractionbetweenresidentcommensalmicrobesontheskinandantimicrobialpeptides.Infact,thereappearstobeadegreeofmicrobialsymbiosiswiththeinnateimmunesys-tem.Forexample,Staphylococcusepidermidisinnormalskincauseskeratinocytestoproduceantimicrobialpeptides,andthesesuppresscytokinereleaseafterminorepidermalinjury.Thus,S.epidermidiscontributesasabarrieragainstcoloniza-

特应性皮炎的流行病学和发病机理

ADepidemiologyandpathogenesisupdate

tionofpathogenicmicrobes.17ThisbegsthequestionofhowS.aureushasdevelopedcolonizationinADskin,aswellasthepossiblesequenceofeventsthatchangesthestandardcom-mensalmicrobesinthispatientpopulation.

Conclusion

ADisacommonskindisease,anditsprevalencecontinuestoincreaseworldwide.Overthepast2decades,researchre-gardingthepathogenesisofADandrelatedconditionshasimplicatedskinbarrierdysfunctionand,inturn,thatmuta-tionsintheFLGadverselyaffectbarrierfunction.Theemerg-ingdataonfundamentaldefectsinbarrierfunctionhaveraisedthequestionofwhetherthesebarrierdefectsallowsecondarychangesinimmunologicresponsethatmediatethedevelopmentofbothADandotheratopicconditions.Thisincreasingbodyofknowledgealsohasfueledinterestinwhetherearlyinterventionscouldmodulatethedevelopmentofthesecondaryatopicphenomena.

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